Helicobacter pylori
Original research
► Additional supplemental
material is published online
only. To view, please visit the
journal online (http://​dx.​doi.​org/​
10.​1136/​gutjnl-​2021-​326583).
1
Leeds Gastroenterology
Institute, Leeds Teaching
Hospitals NHS Trust, Leeds, UK
2
Leeds Institute of Medical
Research, University of Leeds,
Leeds, UK
3 likely to arise from eradication of H. pylori.
Division of Gastroenterology
and Hepatology, Johns Hopkins
University School of Medicine,
Baltimore, Maryland, USA
4
Farncombe Family Digestive
Health Research Institute,
McMaster University, Hamilton,
Ontario, Canada
Correspondence to
Professor Alexander C Ford,
Leeds Gastroenterology
Institute, Leeds Teaching
Hospitals NHS Trust, Leeds,
Leeds, UK;
​alexf12399@​yahoo.​com
Received 16 November 2021
Accepted 29 December 2021
Published Online First
12 January 2022
© Author(s) (or their
employer(s)) 2022. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Ford AC, Tsipotis E,
Yuan Y, et al. Gut
2022;71:1967–1975.
Efficacy of Helicobacter pylori eradication therapy for
functional dyspepsia: updated systematic review
and meta-­analysis
Alexander C Ford ‍ ‍,1,2 Evangelos Tsipotis,3 Yuhong Yuan,4 Grigorios I Leontiadis,4
Paul Moayyedi4
ABSTRACT
Objective Functional dyspepsia (FD) is a chronic
disorder that is difficult to treat. Helicobacter pylori may
contribute to its pathophysiology. A Cochrane review
from 2006 suggested that eradication therapy was
beneficial, but there have been numerous randomised
controlled trials (RCTs) published since. We evaluated
impact of eradication therapy on both cure and
improvement of FD, as well as whether any benefit was
Design We searched the medical literature through
October 2021 to identify RCTs examining efficacy of
eradication therapy in H. pylori-­positive adults with
FD. The control arm received antisecretory therapy or
prokinetics, with or without placebo antibiotics, or
placebo alone. Follow-­up was for ≥3 months. We pooled
dichotomous data to obtain a relative risk (RR) of
symptoms not being cured or symptoms not improving
with a 95% CI. We estimated the number needed to
treat (NNT).
Results Twenty-­nine RCTs recruited 6781 H. pylori-­
positive patients with FD. Eradication therapy was
superior to control for symptom cure (RR of symptoms
not being cured=0.91; 95% CI 0.88 to 0.94, NNT=14;
95% CI 11 to 21) and improvement (RR of symptoms
not improving=0.84; 95% CI 0.78 to 0.91, NNT=9;
95% CI 7 to 17). There was no significant correlation
between eradication rate and RR of FD improving or
being cured (Pearson correlation coefficient=−0.23,
p=0.907), but the effect was larger in patients with
successful eradication of H. pylori than with unsuccessful
eradication (RR=0.65; 95% CI 0.52 to 0.82, NNT=4.5,
95% CI 3 to 9). Adverse events (RR=2.19; 95% 1.10
to 4.37) and adverse events leading to withdrawal
(RR=2.60; 95% CI 1.47 to 4.58) were more common
with eradication therapy.
Conclusion There is high quality evidence to suggest
that H. pylori eradication therapy leads to both cure and
improvement in FD symptoms, although the benefit is
modest.
INTRODUCTION
Functional dyspepsia (FD) is a disorder of gut–brain
interaction (DGBI) whose symptoms are thought
to arise from the gastroduodenum.1 The cardinal
symptoms consist of epigastric pain or burning, early
satiety, or postprandial fullness. FD is diagnosed in
individuals who fulfil symptom-­based criteria, the
Ford AC, et al. Gut 2022;71:1967–1975. doi:10.1136/gutjnl-2021-326583
Significance of this study
What is already known about this subject?
⇒ Helicobacter pylori colonises the stomach of
approximately 50% of the world’s population,
and is implicated in the pathophysiology of
functional dyspepsia (FD).
⇒ However, randomised controlled trials (RCTs)
of eradication therapy for the treatment of H.
pylori-­positive patients with FD demonstrate
conflicting results.
⇒ It is unclear whether any potential benefit of
eradication therapy stems from eradication of
H. pylori or from other effects of antibiotics on
the upper gastrointestinal microbiome.
What are the new findings?
⇒ Eradication therapy had a significant benefit
both on cure of symptoms (relative risk (RR)
of symptoms not being cured=0.91; 95%
CI 0.89 to 0.94, number needed to treat
(NNT)=14; 95% CI 11 to 21), and improvement
in symptoms (RR of symptoms not
improving=0.84; 95% CI 0.78 to 0.91, NNT=9;
95% CI 7 to 17).
⇒ This effect remained stable through multiple
subgroup analyses.
⇒ The treatment effect was larger, compared with
control therapy, in patients with successful
eradication of H. pylori (RR of symptoms not
being cured=0.74; 95% CI 0.64 to 0.85, NNT=6;
95% CI 4 to 10).
How might it impact on clinical practice in the
foreseeable future?
⇒ Our updated systematic review and meta-­
analysis provides high quality evidence that
eradication therapy is an efficacious treatment
for H. pylori-­positive patients with FD.
⇒ With inclusion of data from almost 7000
patients, almost 3000 of whom were in newly
identified RCTs, our confidence in the estimate
of effect has improved, and the magnitude of
the effect has increased slightly.
Rome IV criteria, in the absence of a structural
explanation.2 The prevalence of FD in the commu-
nity, according to these criteria, is approximately
   1967
 Helicobacter pylori
7%.3 4 In the majority of individuals, symptoms are chronic and
run a relapsing and remitting course.5 The condition, therefore,
affects quality of life and social functioning6 7; almost 50% of
patients would accept a >12% risk of sudden death in return
for a 99% chance of cure.8 There is also a substantial economic
impact, estimated at over $18 billion per year in the USA.9
The pathophysiology of FD is complex, multifactorial and
incompletely understood.10Helicobacter pylori, which colonises
the stomach of approximately 50% of the world’s population,11
may be implicated. Numerous epidemiological studies demon-
strate that H. pylori infection is associated with dyspepsia in the
community, most of which will be due to FD,12 but the magni-
tude of this association is modest.13 14 Nevertheless, randomised
controlled trials (RCTs) show that eradication of the bacte-
rium significantly reduces the prevalence of dyspepsia in the
community.15 16 In contrast, RCTs of eradication therapy in H.
pylori-­positive patients with FD have demonstrated conflicting
results,17–20 although this may be because the benefit is small and
some trials were underpowered to detect a significant differ-
ence. In a prior Cochrane collaboration systematic review and
meta-­analysis eradication therapy had a statistically significant
benefit, in terms of symptom cure or improvement in H. pylori-­
positive patients with FD, and appeared to be cost effective.21 22
However, the effect was relatively modest, based on the number
needed to treat (NNT), which was reported as 14. Neverthe-
less, H. pylori eradication therapy is recommended for infected
patients with FD.23
It is 15 years since the last update of this meta-­analysis, and
there have been further studies published in the intervening
years. In addition, it remains unclear whether the benefit of
eradication therapy in H. pylori-­positive FD relates to cure of the
infection. Murine models demonstrate that H. pylori infection
induces sensorimotor changes in the stomach similar to those
seen in patients with FD, which are normalised by eradication of
the infection.24 However, studies suggest that there is duodenal
inflammation in FD,25 26 and alterations in the duodenal micro-
biota may also be implicated in its pathophysiology.27 It could,
therefore, be the case that the antibiotics used as part of H.
pylori eradication therapy are exerting beneficial effects via the
treatment of other organisms.28 Indeed, antibiotics appear to be
beneficial in other DGBI, such as irritable bowel syndrome,29 30
and in a small RCT from Hong Kong rifaximin, a minimally
absorbed broad-­spectrum antibiotic, was superior to placebo for
the treatment of H. pylori-­negative FD.31
We, therefore, updated the previous systematic review and
meta-­analysis.21 22 Our aims were to re-­ examine efficacy of
eradication therapy for the treatment of H. pylori-­positive
FD, incorporating new RCTs, as well as to assess if any effect
is related to the impact of antibiotics on upper gastrointestinal
tract microbiota in general or whether this is specific to eradi-
cation of H. pylori. We assessed this by evaluating whether the
efficacy of eradication therapy was influenced by eradication
rates achieved, the antibiotics used, or whether eradication of H.
pylori was successful or not.
METHODS
Search strategy and study selection
We updated the previous Cochrane review and meta-­analysis
examining this issue.21 22 We searched MEDLINE (1946 to
October 2021), EMBASE and EMBASE Classic (1947 to October
2021), and the Cochrane Central Register of Controlled Trials
to identify potential studies. In addition, we searched ​clinical-
trials.​gov. We hand searched conference proceedings (Digestive
1968
Diseases Week, American College of Gastroenterology, United
European Gastroenterology Week and the Asian Pacific Diges-
tive Week) between 2006 and 2021 to identify studies published
only in abstract form. Finally, we performed a recursive search
of the bibliographies of all eligible studies.
Eligible RCTs examined the effect of ≥1 week of eradication
therapy on symptoms of FD in H. pylori-­positive adults (≥16
years) (online supplemental table 1). Trials had to compare a
recognised, efficacious, eradication therapy with antisecretory
therapy or prokinetics, with or without placebo antibiotics or
a placebo alone. The diagnosis of FD could only be made after
a normal upper gastrointestinal endoscopy and was based on
either accepted symptom-­based diagnostic criteria or a physi-
cian’s opinion. We required that subjects be followed up for ≥3
months, and trials had to report either cure or improvement of
FD symptoms at the last point of follow-­up. This was preferably
patient reported, but if not then as documented by the investi-
gator or via questionnaire data.
The literature search was conducted by two investigators (YY
and ET), independently from each other. The search strategy
we used is detailed in the online supplemental materials. We
evaluated all abstracts identified by the search. Again, this was
done by two investigators (YY and ET) independently from each
other. We obtained all potentially relevant papers and evaluated
them in more detail, using predesigned forms, to assess eligibility
independently, according to the predefined criteria. We resolved
disagreements between investigators by discussion. There were
no language restrictions; we translated foreign language papers.
Chinese language papers were translated and, if they reported
definite evidence of a randomisation process, were included.
Outcome assessment
Our primary outcome was the effect of H. pylori eradication
therapy, compared with antisecretory therapy or prokinetics,
with or without placebo antibiotics, or a placebo alone on
cure or improvement of FD symptoms. Secondary outcomes
included effect of H. pylori eradication therapy on FD symptoms
according to eradication rates, success or failure of eradication
therapy and antibiotics used, as well as total number of adverse
events occurring due to therapy, and adverse events leading to
study withdrawal, if reported.
Data extraction
We extracted all data independently. This was done by two inves-
tigators (YY and ET) onto a Microsoft Excel spreadsheet (XP
professional edition; Microsoft Corp, Redmond, Washington,
USA) as dichotomous outcomes (FD symptoms not improved or
not cured). A third investigator (ACF) also extracted all trials
independently and compared this with the final data extraction
as agreed by the first two investigators. Any disagreements were
resolved by consensus (PM, ACF, and YY). To study the effect
of eradication therapy on FD symptoms according to success or
failure of H. pylori eradication, we also extracted data in the
active H. pylori eradication therapy arms of the trial according
to final H. pylori status, where reported. For all included studies,
we also extracted the following data for each trial, where avail-
able: country of origin, setting, number of centres, criteria
used to define FD, method used to confirm H. pylori infection,
type of H. pylori eradication regimen used (including dose and
schedule of individual drugs within it), duration of treatment,
eradication rate, duration of follow-­up, total number of adverse
events and number of adverse events leading to withdrawal.
We extracted all data as intention-­to-­treat analyses, where we
Ford AC, et al. Gut 2022;71:1967–1975. doi:10.1136/gutjnl-2021-326583

assumed all dropouts to be treatment failures (ie, symptoms not
cured or not improved at last point of follow-­up), wherever trial
reporting allowed this.
Quality assessment and risk of bias
We assessed risk of bias at the study level. This was done by two
investigators independently (YY and ET), using the Cochrane
risk of bias tool.32 We resolved disagreements by discussion.
We recorded the method used to generate the randomisation
schedule and conceal treatment allocation, whether blinding
was implemented for participants, personnel and outcomes
assessment, whether there was evidence of incomplete outcomes
data and whether there was evidence of selective reporting of
outcomes.
Data synthesis and statistical analysis
We used a random effects model to pool data,33 to give a more
conservative estimate of the efficacy of eradication therapy in
H. pylori-­positive patients with FD. We expressed the impact
of eradication therapy, compared with antisecretory therapy or
prokinetics, with or without placebo antibiotics, or a placebo
alone as a relative risk (RR) of symptoms not being cured, or
symptoms not improving, separately along with 95% CIs. We
used an RR of symptoms not being cured, or symptoms not
improving, where if the RR was less than 1 and 95% CI did
not cross 1, there was a significant benefit of H. pylori eradi-
cation therapy over the control intervention. This approach is
the most stable, compared with an RR of cure or improvement,
or using the odds ratio, for some meta-­analyses.34 Similarly, we
summarised adverse events data with RRs and 95% CIs. We
calculated the NNT, and the number needed to harm (NNH),
with a 95% CI, using the formula NNT or NNH=1/(assumed
control risk×(1–RR)).
We assessed heterogeneity between studies using both the χ2
test, with a p value <0.10 used to define a significant degree
of heterogeneity, and the I2 statistic. The I2 ranges between 0%
and 100%, and is typically considered low, moderate or high
for values of 25%–49%, 50%–74% and ≥75%, respectively.35
Review Manager V.5.4.1 (RevMan for Windows 2020, the
Nordic Cochrane Centre, Copenhagen, Denmark) was used to
generate forest plots of pooled RRs for primary and secondary
outcomes with 95% CIs, as well as funnel plots. Where there
were sufficient studies (≥10),36 we assessed funnel plots for
evidence of asymmetry and, therefore, possible publication bias
or other small study effects, using the Egger test.37
Figure 1 Forest plot of RCTs of H. pylori eradication therapy: effect on symptom cure in FD. FD, functional dyspepsia; H. pylori, Helicobacter pylori;
RCTs, randomised controlled trials.
Ford AC, et al. Gut 2022;71:1967–1975. doi:10.1136/gutjnl-2021-326583
Helicobacter pylori
Due to differences in the control interventions used in eligible
trials, we performed a subgroup analysis limited to RCTs that
compared H. pylori eradication therapy to antisecretory therapy
and placebo antibiotics, or a placebo alone. We also performed
subgroup analyses including only low risk of bias trials, according
to study location (Asian vs non-­Asian studies), and according
to duration of follow-­ up (12 months versus <12 months).
To examine the effect of H. pylori eradication therapy on FD
symptoms according to either success or failure of eradication
therapy, and antibiotic used, we performed subgroup analyses.
We compared rates of cure or improvement of symptoms in
patients with successful or unsuccessful eradication therapy with
those in the control arm, as well as with each other. We also
pooled trials according to the antibiotic used as part of the erad-
ication therapy regimen and assessed whether there were statis-
tically significant differences between them according to the χ2
test.
RESULTS
The search identified 6687 citations, of which 29 trials, recruiting
6781 patients, reported dichotomous symptom data, and were
judged as being eligible for inclusion (online supplemental
figure 1).17–20 38–62 Ten of these trials, recruiting 2896 patients,
were identified since the previous systematic review and meta-­
analysis.53–62 In total, 3625 patients were randomised to receive
H. pylori eradication therapy and 3156 antisecretory therapy or
prokinetics, with or without placebo antibiotics, or a placebo
alone. Characteristics of all included trials are provided in online
supplemental table 2. Risk of bias assessment of all included
RCTs is provided in online supplemental table 3. We classed six
trials as being at low risk of bias across all domains.20 43 49 55 58 62
Effect of H. pylori eradication therapy on FD symptoms
In total, there were 18 RCTs reporting on cure of symp-
toms,17–20 42 43 45 47 48 50 51 53–59 which recruited 4564 H. pylori-­
positive patients with FD, 2432 of whom received eradication
therapy. The RR of FD symptoms not being cured with eradi-
cation therapy versus control was 0.91 (95% CI 0.88 to 0.94)
(figure 1), with minimal heterogeneity between studies (I2=7%,
p=0.38). However, the funnel plot was asymmetrical, suggesting
evidence of publication bias or other small study effects (Egger
test, p=0.083). The NNT was 14 (95% CI 11 to 21). When
we limited the analysis to only the 14 studies, containing
3903 patients,17–20 42 43 45 47 48 50 55 57–59 that compared eradi-
cation therapy with either antisecretory therapy with placebo
1969
 Helicobacter pylori
Figure 2 Forest plot of RCTs of H. pylori eradication therapy: effect on symptom improvement in FD. FD, functional dyspepsia; H. pylori, Helicobacter
pylori; RCTs, randomised controlled trials.
antibiotics, or placebo alone, the RR of symptoms not improving
was 0.91 (95% CI 0.89 to 0.94), with an NNT of 14 (95%
CI 12 to 22) with no heterogeneity between studies (I2=0%,
p=0.80), and no evidence of funnel plot asymmetry (Egger test,
p=0.24). When the eight RCTs that compared antisecretory
therapy and placebo antibiotics with eradication therapy were
included,17 42 43 45 47 48 58 59 there was still a benefit (RR=0.92;
95% CI 0.88 to 0.96, I2=0%, p=0.73), with an NNT of 16 (95%
CI 11 to 33). Similarly, when only the six trials that compared
placebo alone with eradication therapy were included,18–20 50 55 57
the benefit remained (RR=0.91; 95% CI 0.87 to 0.96, I2=0%,
p=0.47) with an NNT of 14 (95% CI 10 to 31).
There were 22 trials that reported on improvement of FD
symptoms,18–20 38–41 44–47 49–54 57 58 60–62 randomising 5193 H.
pylori-­positive patients with FD, 2824 of whom received erad-
ication therapy. The RR of FD symptoms not improving with
eradication therapy versus control was 0.84 (95% CI 0.78
to 0.91) (figure 2), with moderate heterogeneity between
studies (I2=69%, p<0.001). The funnel plot was symmetrical,
suggesting no evidence of publication bias or other small study
effects (Egger test, p=0.16). The NNT was 9 (95% CI 7 to 17).
When we limited the analysis to only 16 studies, containing
4224 patients,18–20 38 39 41 44–47 49 50 57 58 61 62 that compared erad-
ication therapy with either antisecretory therapy with placebo
antibiotics or placebo alone, the RR of symptoms not improving
was 0.86 (95% CI 0.79 to 0.94), with an NNT of 10 (95% CI
7 to 24). Moderate heterogeneity between studies persisted
(I2=71%, p<0.001), but there was no evidence of funnel plot
asymmetry (Egger test, p=0.46). Eight of these trials compared
antisecretory therapy and placebo antibiotics with eradication
therapy (RR=0.83; 95% CI 0.73 to 0.95, I2=81%, p<0.001;
NNT=8; 95% CI 5 to 27),38 39 44–47 58 61 and eight compared
placebo alone with eradication therapy (RR=0.90; 95% CI 0.80
to 1.00, I2=49%, p=0.06).18–20 41 49 50 57 62
Pooling data from all 29 RCTs, irrespective of whether they
reported symptom cure or improvement, but using symptom
cure preferentially, where reported, the RR of symptoms not
being cured or not improving with H. pylori eradication therapy
versus control was 0.87 (95% CI 0.83 to 0.92), with moderate
heterogeneity between studies (I2=64%, p<0.001) (online
supplemental figure 2). Again, the funnel plot was asymmetrical,
suggesting evidence of publication bias or other small study
effects (Egger test, p=0.014). The NNT was 10 (95% CI 8 to
1970
16). Limiting the analysis to only the six RCTs at low risk of bias
still demonstrated a significant effect of H. pylori eradication
therapy (RR of symptoms not being cured or improving=0.90;
95% CI 0.81 to 0.99, I2=46%, p=0.10) (online supplemental
figure 3),20 43 49 55 58 62 with an NNT of 14 (95% CI 7 to 139).
When we performed a subgroup analysis based on study loca-
tion, the effect of H. pylori eradication therapy was greater in
Asian studies (RR=0.82; 95% CI 0.73 to 0.91, NNT=8; 95% CI
5 to 15, I2=77%, p<0.001) compared with non-­Asian studies
(RR=0.92; 95% CI 0.89 to 0.95, NNT=16; 95% CI 12 to 25,
I2=11%, p=0.32) and this difference was statistically significant
(p value for χ2=0.04) (online supplemental figure 4). Finally,
when we performed a subgroup analysis based on study dura-
tion, a beneficial effect on FD symptoms was seen in studies of
12-­month duration (RR=0.87; 95% CI 0.82 to 0.92, NNT=10;
95% CI 7 to 17, I2=65%, p<0.001), but not studies of <12-­
month duration (RR=0.88; 95% CI 0.77 to 1.00, I2=67%,
p=0.01) (online supplemental figure 5), but this difference was
not statistically significant (p value for χ2=0.87).
Effect of H. pylori eradication therapy on FD symptoms
according to eradication rates, success or failure of
eradication therapy, and antibiotics used
To assess whether the beneficial effect of eradication therapy
was due to eradication of H. pylori or an effect related to the
use of antibiotics in general, or a particular antibiotic, we first
assessed for any correlation between eradication rates observed
in the trials and rates of symptom cure or improvement using a
Pearson correlation coefficient. There was no significant correla-
tion between the two (Pearson correlation coefficient=−0.23,
p=0.907) (figure 3).
Second, we compared rates of symptom cure or improve-
ment according to whether H. pylori was eradicated success-
fully in patients in the trial arms that received active H.
pylori eradication therapy. In these analyses, there were 16
RCTs,18 19 38 40 41 43 48–50 54–57 59–61 containing 2809 patients,
where symptom cure or improvement rates could be compared
between patients with successful eradication of H. pylori and
patients in the control arms. The RR of symptoms not being
cured or not improving with successful H. pylori eradication
therapy versus control therapy was 0.74 (95% CI 0.64 to 0.85,
I2=82%, p<0.001) (figure 4), and with evidence of funnel plot
Ford AC, et al. Gut 2022;71:1967–1975. doi:10.1136/gutjnl-2021-326583
 Helicobacter pylori

Figure 3 Scatterplot of H. pylori eradication rate versus rate of symptom cure or improvement in individual RCTs. H. pylori, Helicobacter pylori; RCTs,
randomised controlled trials.

asymmetry (Egger test, p=0.076). The NNT was 6 (95% CI 4
to 10). Thirteen trials,19 38 40 41 43 48 49 55–57 59–61 containing 1517
patients, provided data comparing symptom cure or improve-
ment rates between patients with unsuccessful eradication of H.
pylori and patients in the control arms. In this analysis, the RR
of symptoms not being cured or not improving with unsuccessful
H. pylori eradication therapy versus control therapy was 1.02
(95% CI 0.96 to 1.09, I2=0%, p=0.63) (online supplemental
figure 6), with no evidence of funnel plot asymmetry (Egger
test, p=0.75). These same 13 RCTs,19 38 40 41 43 48 49 55–57 59–61
containing data from 1259 patients, compared symptom cure
or improvement rates between patients receiving eradication
therapy with successful or unsuccessful eradication of H. pylori.
The RR of symptoms not being cured or not improving with
successful versus unsuccessful eradication of H. pylori was 0.65
(95% CI 0.52 to 0.82, I2=79%, p<0.001) (figure 5), with no
evidence of funnel plot asymmetry (Egger test, p=0.20). The
NNT in this analysis was 4.5 (95% CI 3 to 9).
Finally, we compared efficacy of eradication therapy with
control therapy according to the eradication regimen or anti-
biotics used (table 1). NNTs were lower, generally, with
nitroimidazole-­containing regimens, and in regimens consisting
of a proton pump inhibitor (PPI) in combination with either
amoxicillin and a nitroimidazole, or clarithromycin and a
nitroimidazole.
Given this, we assessed for differences in efficacy across
all nitroimidazole-­containing and non-­ containing regimens,
as well as nitroimidazole-­containing and non-­ containing PPI
triple therapy regimens (online supplemental figures 7 and 8).
However, there were no significant differences between these
subgroup analyses according to the χ2 test (p=0.10 and p=0.17,
respectively).
Adverse events
Adverse events data were reported incompletely by most trials.
Only eight RCTs reported total numbers of adverse events, in
1937 patients.19 41 45 46 48 52 56 58 Overall, adverse events were
significantly more common with eradication therapy (RR=2.19;
95% CI 1.10 to 4.37), with high levels of heterogeneity between
studies ((I2=92%, p<0.001) (online supplemental figure 9)
and an NNH of 3 (95% CI 1 to 40). Adverse events leading
to withdrawal were reported by 18 trials, recruiting 3694
patients.18–20 38 39 41–43 45–47 49 50 52 53 55–57 Withdrawals due to
adverse events were also significantly more likely with erad-
ication therapy (RR=2.60; 95% CI 1.47 to 4.58), with no

Figure 4 Forest plot of RCTs of H. pylori eradication therapy: effect on symptom cure or improvement in FD in those with successful H. pylori
eradication therapy versus control therapy. FD, functional dyspepsia; H. pylori, Helicobacter pylori; RCTs, randomised controlled trials.
Ford AC, et al. Gut 2022;71:1967–1975. doi:10.1136/gutjnl-2021-326583 1971
 Helicobacter pylori

Figure 5 Forest plot of RCTs of H. pylori eradication therapy: effect on symptom cure or improvement in FD in those with successful H. pylori
eradication therapy versus unsuccessful H. pylori eradication therapy. FD, functional dyspepsia; H. pylori, Helicobacter pylori; RCTs, randomised
controlled trials.

heterogeneity between studies (I2=0%, p=0.66) (online supple-
mental figure 10) and an NNH of 71 (95% CI 32 to 242). There
was no evidence of funnel plot asymmetry (Egger test, p=0.62).
DISCUSSION
This updated systematic review and meta-­analysis has confirmed
that eradication therapy is efficacious for the treatment of FD
in H. pylori-­positive patients. The RR of either symptoms not
being cured or symptoms not improving was significantly lower
than with a control intervention, with an NNT of 14 and 9,
respectively. Adverse events were more common with eradi-
cation therapy, as were adverse events leading to withdrawal,
although reporting of these data was incomplete in many trials.
Although the effect on cure of symptoms was modest, when
applied to entire healthcare systems, and for a highly preva-
lent condition, this is likely to lead to substantial reductions in
management costs. Eradication therapy is particularly likely to
be cost effective as a 2-­week course of treatment has an impact
for at least 12 months. We judged the evidence for efficacy and
safety of eradication therapy in H. pylori-­positive patients with
FD as high quality (online supplemental table 4).
Whether this relates to the eradication of H. pylori or a more
general impact on the upper gastrointestinal tract microbiota is
unclear from our data. There was no correlation between H.
pylori eradication rates and rates of symptom cure or improve-
ment, which suggests the effect may relate to a general impact
on the gut microbiota. This analysis has the advantage that all
data are evaluated and so publication bias is less likely, but as
trial level data are being used it is possible that the results are
confounded by trial level factors. On the other hand, the RR
of FD symptoms not being cured or not improving was signifi-
cantly lower in those patients receiving eradication therapy who
had successful eradication of H. pylori, compared with either
patients receiving a control intervention or patients randomised
to eradication therapy in whom eradication was unsuccessful,
with an NNT of 6 and 4.5, respectively, which appear more
impressive. This suggests a specific effect of the eradication
regimen on H. pylori, although over half the trials did not
report these data, so publication bias is probable. Also, patients
remaining H. pylori-­positive are likely to be different to those
with successful eradication, and so these results may also be due
to bias or confounding. For instance, patients in whom eradica-
tion of H. pylori was unsuccessful may be less likely to adhere to
the trial medication, and hence did not receive antibiotics at all.
Finally, NNTs were lower with H. pylori eradication regimens
containing a nitroimidazole, although these differences in effi-
cacy were not statistically significant.

Table 1 Relative risk of symptoms not being cured or not improving and NNT according to H. pylori eradication regimen used
RR of symptoms not being
Number of cured or not improving NNT P value
H. pylori eradication regimen used Number of trials patients (95% CI) (95% CI) I2 for χ2
Amoxicillin containing 25 6076 0.91 15 19% 0.20
(0.88 to 0.94) (11 to 22)
Clarithromycin containing 22 5577 0.87 10 67% <0.001
(0.82 to 0.92) (7 to 17)
Nitroimidazole containing 8 1589 0.79 6.5 86% <0.001
(0.67 to 0.93) (4 to 18.5)
Tetracycline containing 2 223 0.54 N/A 88% 0.005
(0.16 to 1.77)
PPI, amoxicillin and clarithromycin 17 4159 0.92 16.5 0% 0.61
(0.89 to 0.95) (12 to 26.5)
PPI, amoxicillin and nitroimidazole 2 469 0.87 8.5 0% 0.33
(0.81 to 0.94) (6 to 18)
PPI, clarithromycin and nitroimidazole 2 482 0.68 4 89% 0.003
(0.47 to 0.98) (2 to 57)
PPI triple therapy containing a 5 1112 0.80 6 86% <0.001
nitroimidazole (0.66 to 0.97) (4 to 40)
N/A, not applicable, as no significant benefit of treatment ; NNT, number needed to treat; PPI, proton pump inhibitor.

1972 Ford AC, et al. Gut 2022;71:1967–1975. doi:10.1136/gutjnl-2021-326583


We updated a previous meta-­analysis from 2006, using a
contemporaneous and exhaustive search strategy, and identi-
fied 10 new eligible RCTs, containing almost 3000 patients.
Despite this, the estimate of the efficacy of eradication therapy,
in terms of cure or improvement of symptoms, remains rela-
tively unchanged from the last version of this meta-­analysis.22
However, in this updated meta-­analysis, we studied the effect
of H. pylori eradication therapy on cure or improvement
of symptoms separately. Although the NNT of 14 for cure
of symptoms is modest, the NNT of 9 for improvement in
symptoms is of a similar magnitude to that for other drugs in
FD.63–66 Data extraction was undertaken in triplicate. We used
a random effects model and an intention-­to-­treat analysis, to
minimise the possibility that the effect of eradication therapy
on symptoms of FD has been overestimated. In addition, all
trials had a minimum duration of follow-­ up of 3 months,
and only six trials reported data at less than 12 months of
follow-­up,41 43 48 51 52 57 meaning that the data we report are
likely to indicate long-­term efficacy. In fact, in a subgroup anal-
ysis based on study duration, the effect for symptom cure or
improvement increased, with an NNT of 10, when only trials
of 12 months duration were included, whereas when RCTs of
<12-­month duration were included there was no significant
benefit. Although the difference between these subgroup anal-
yses was not statistically significant, this suggests that future
trials should aim to follow participants up for 12 months in
order to assess any benefit of eradication therapy in H. pylori-­
positive FD.
Limitations of this meta-­analysis include the fact that only
six trials were classed as being at low risk of bias across all
domains, although a subgroup analysis, including only these
RCTs, still demonstrated a significant effect of H. pylori
eradication therapy in FD. This means that the quality of
evidence underpinning our estimates is of high quality. There
was heterogeneity between studies examining the effect of H.
pylori eradication therapy on symptom improvement, meaning
that there is uncertainty in our estimates. This was minimal or
low in some of our subgroup analyses based on the compar-
ator regimen, the eradication therapy regimen used and study
location. There was also evidence of publication bias, or other
small study effects, in some of our analyses. The eradication
regimens used varied considerably between the individual
trials and PPI dual therapy or ranitidine bismuth citrate triple
therapy would now be considered ‘historical’. However, if
anything, suboptimal eradication rates associated with these
older regimens may have led to an underestimate of the effi-
cacy of eradication therapy on FD symptoms. In addition, the
control intervention also varied between individual trials, from
placebo alone, antisecretory therapy plus placebo antibiotics,
prokinetics or antacids. Blinding in some of these RCTs would
not have been possible, and these differences in trial design
may have contributed to the heterogeneity observed, although
results were similar in subgroup analyses, including only trials
that compared H. pylori eradication therapy with antise-
cretory therapy plus placebo antibiotics or a placebo alone.
Adverse events data were not reported by many of the RCTs
we identified, meaning that balancing the benefits and harms
of eradication therapy in treating H. pylori-­positive patients
with FD is difficult. Finally, our analyses based on success or
failure of eradication therapy, although novel and potentially
interesting, were not based on the randomised groups and may
have inherent confounding and, in some cases, biases.
Despite these limitations, our results suggest that it is worth-
while testing patients with FD and eradicating the infection
Ford AC, et al. Gut 2022;71:1967–1975. doi:10.1136/gutjnl-2021-326583
Helicobacter pylori
if present. With an NNT of 14 for cure of symptoms, this is
likely to be cost effective,21 and there are other benefits from
eradication of H. pylori, including a reduction in the future
incidence of peptic ulcer and gastric cancer,67–70 as well as the
costs of managing these conditions.71 72 There is also evidence
that testing for and treating H. pylori in patients with uninves-
tigated dyspepsia in the community, the majority of whom will
have FD,12 leads to a significant reduction in the likelihood of
needing upper gastrointestinal endoscopy,73 which is one of
the main drivers of the costs of managing dyspepsia. In addi-
tion, FD is common,3 4 and other treatments are only modestly
efficacious in improving symptoms,63–66 need to be taken long-­
term and some, such as prokinetics, are not available in many
countries. On the other hand, a course of H. pylori eradication
therapy only needs to be taken for 2 weeks, and the drugs that
are its constituent components are cheap and available widely.
There have been further meta-­ analyses conducted since
the original Cochrane review examining this issue.21 22 Our
updated meta-­analyses contains more trials and more patients
that either of the two most recent.74 75 Similar to our results,
these demonstrated modest benefits of eradication therapy in
FD with an increase in adverse events with active treatment,
and a greater benefit with increasing duration of follow-­up.
One of these meta-­analyses reported that the NNT was 15,
but also suggested that there was no significant benefit of erad-
icating H. pylori in Asian patients with FD.75 However, the
95% confidence around the estimate of efficacy in this meta-­
analysis was almost significant. Our results are likely to differ
because we included data from a further 11 RCTs. We are not
aware of these other meta-­analyses having tried to elucidate
whether the benefit of eradication therapy stems from the
successful eradication of H. pylori or the use of antibiotics in
general. Another strength of our meta-­analysis is the multiple
subgroup analyses, including those comparing eradication
therapy with both antisecretory therapy and placebo antibi-
otics and placebo alone.
How H. pylori eradication therapy is having its beneficial
effects in FD remains uncertain.28 Whether it is an effect of anti-
biotics, per se, on the gastrointestinal microbiome or an effect
of eradication of H. pylori infection remains unclear. Trials
of eradication therapy versus a PPI and placebo antibiotics in
H. pylori-­negative patients with FD could answer this ques-
tion. Nitroimidazole-­containing regimens and nitroimidazole-­
containing PPI triple therapies appeared to lead to a greater
treatment effect, compared with eradication regimens or
PPI triple therapies without a nitroimidazole, although these
differences were not statistically significant. A small trial of
rifaximin in H. pylori-­negative patients with FD in Hong Kong
demonstrated a significant benefit over placebo,31 but there
have been no other RCTs of antibiotics conducted, to the best
of our knowledge. In addition, follow-­up in this trial was only
for 8 weeks, and whether repeated courses are required, as is
the case in some patients with irritable bowel syndrome,76 is
unknown. An alternative proposed by the Kyoto consensus is
that H. pylori is itself a cause of dyspepsia,77 an organic disease
termed H. pylori-­associated dyspepsia, and only if symptoms
persist after a course of eradication therapy should the patient
be labelled as having FD. However, this is contentious and
based on expert opinion rather than RCT evidence. If H.
pylori eradication were to ‘cure’ dyspepsia in nearly all cases,
it would support this stance, but the impact observed in this
updated meta-­analysis was only modest.
Our updated systematic review and meta-­a nalysis provides
high quality evidence that eradication therapy is an efficacious
1973
 Helicobacter pylori
treatment for H. pylori-­p ositive patients with FD and should,
therefore, be first-­line therapy in such patients. The NNT
for symptom cure was 14, and for symptom improvement it
was 9. With the inclusion of data from almost 7000 patients,
almost 3000 of whom were in newly identified RCTs, our
confidence in the estimate of effect has improved, and the
magnitude of the effect has increased slightly. It is likely that
this would be a cost-­e ffective treatment for FD, and it would
only need to be applied as a single intervention. It remains
unclear how eradication therapy is having its benefits in
FD. Future RCTs should consider assessing the efficacy of
eradication therapy in patients with FD without H. pylori
infection.
Acknowledgements We are grateful to Dr Premysl Bercik for assistance with
translation of foreign language articles.
Contributors ACF, ET, GIL, YY and PM conceived and drafted the study. ACF, ET,
YY and PM collected all data and analysed and interpreted the data. ACF, YY and
PM drafted the manuscript. All authors commented on drafts of the paper and
have approved the final draft of the manuscript. ACF is guarantor. He accepts full
responsibility for the work and the conduct of the study, had access to the data and
controlled the decision to publish. The corresponding author attests that all listed
authors meet authorship criteria and that no others meeting the criteria have been
omitted.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Not applicable.
Ethics approval This study involves human participants but was not approved by
any institution as it is a meta-­analysis of existing randomised controlled trials.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available. Not applicable.
Supplemental material This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
ORCID iD
Alexander C Ford http://orcid.org/0000-0001-6371-4359
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